PROJECT SUMMARY Despite the advent of safer antiretroviral therapy agents with low potential for mitochondrial toxicity, accumulation of central and ectopic fat remains a common and significant challenge facing HIV providers and threatens the well-being of individuals living with HIV. Limited progress has been made in understanding and managing lipohypertrophy. Initially linked to the use of protease inhibitors, we have recently reported similar gains in peripheral and central fat after initiation of successful HIV treatment with both protease inhibitors and integrase inhibitors. These observations have challenged current beliefs and raised the concerns that fat accumulation may indeed be due to HIV itself, directly and/or indirectly, through the heightened inflammatory state that accompanies HIV. The role of alteration in gut hormone secretion and gut epithelial barrier dysfunction in HIV-associated metabolic disorders is largely unknown, but it is plausible since chronic inflammation (such as that seen in HIV) has been shown to affect the secretion of gut hormones. Studies of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in diabetics have shown them to be safe, well-tolerated, with very low to no concerns about drug-drug interactions, and, importantly, have caused weight loss that appear to occur, at least in some studies, preferentially via losses in visceral fat. Some GLP- 1RAs have even shown to decrease clinical CVD events in diabetics. Thus, this promising class of drugs may offer a powerful tool to fight the triple threat facing the success of long-term HIV treatment: namely, 1) excess fat accumulation and ectopic fat deposition, 2) insulin resistance and a high prevalence of diabetes, and 3) endothelial dysfunction and cardiovascular disease (CVD) risk. GLP-1RAs act by partially-delineated mechanisms, several of which will be studied in this proposal. We will conduct a randomized, double-blinded, placebo-controlled clinical trial to assess whether a potent and safe GLP-1RA may positively affect visceral fat and ectopic fat accumulation, insulin resistance, inflammation markers, and the downstream effect on CVD in people living with HIV. A similarly-designed trial will enroll an HIV-uninfected, obese group, matched to the group with HIV by key factors and will run in parallel. Including a parallel study of people without HIV will be helpful in making significant observations about the specificity of the findings to the HIV population. Major strengths of this study include the extensive experience of the primary site?s principle investigator in leading clinical trials involving cardiometabolic complications in HIV, as well as the expertise and successful collaborative record of the investigative team on HIV-related metabolic complications, CVD risk, and immune activation, as well as GLP-1 physiology, pathophysiology and treatment of obesity and diabetes, and statistical expertise.